Date of Award

4-16-2010

Degree Type

Closed Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

W. David Wilson - Committee Chair

Second Advisor

Claudia Sissi - Committee Member

Third Advisor

David Boykin - Committee Member

Fourth Advisor

Giovanni Gadda - Committee Member

Fifth Advisor

Manlio Palumbo - Committee Member

Sixth Advisor

Markus Germann - Committee Member

Abstract

G-quadruplex structures are found in important regions of the eukaryotic genome, such as telomeres and regulatory sequences of genes, and are likely to play important roles in regulation of biological events. The significant structural differences with duplex DNA make quadruplex DNA a very attractive target for anticancer drug design. The purpose of this study is to explore conformational space in a series of heterocyclic cations to discover novel structural motifs that can selectively bind and stabilize specific G-quadruplex arrangements. A variety of biophysical techniques such as thermal melting experiments, biosensor surface plasmon resonance, circular dichroism, fluorescence displacement assay and mass spectrometry were employed to evaluate the affinity of the compounds and their recognition properties. The screening of the molecules allowed the identification of not only selective G-quadruplex ligands but also potential quadruplex groove binders. These results can be useful for the development of new efficient telomerase inhibitors which are endowed with pharmacological activity.

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